Osteoporosis is unique among chronic conditions in that there is no accepted role for combining medications, even in patients who are at the highest risk of fracture. Both anabolic and antiresorptive osteoporosis therapies increase bone density and reduce fracture incidence but are unable to restore skeletal integrity in most patients with established disease. Attempts to combine the only available anabolic agent (teriparatide) with the most commonly used antiresorptive agents (bisphosphonates) have demonstrated no benefit compared to each drug alone. Conversely, we recently reported that the combination of teriparatide and the nuclear factor-?B ligand inhibitor, denosumab, increases bone density and improves cortical microarchitecture more than each drug alone. This combination shows superior efficacy, at least in part, because denosumab is able to fully block teriparatide's pro-resorptive effects while allowing for continued bone formation. Thus, combining denosumab with a more potent anabolic stimulus may allow for greater separation of formation and resorption and larger improvements in bone mass and strength. To test this hypothesis, we have initiated a 15-month clinical trial to evaluate the therapeutic potential of combining high-dose teriparatide (40-g daily) with denosumab in postmenopausal osteoporotic women. Because the discontinuation of both teriparatide and denosumab are associated with rapid bone loss, if any combination of these medications is to become a widely used treatment approach, strategies to consolidate and expand skeletal improvements must be defined. The aim of the current proposal is to evaluate a rational and cost-effective approach to this consolidation by testing the hypotheses that in postmenopausal women with osteoporosis, the large increases in bone density and improvements in bone quality achieved with combined denosumab/teriparatide therapy will be maintained and extended by a single administration of an intravenous bisphosphonate. Specifically, women who complete the high-dose teriparatide study will be offered enrollment in a single arm 27-month open-label extension. In this extension, women will receive a single 5-mg intravenous dose of zoledronic acid. Bone mineral density will then be assessed by dual-energy X-ray absorptiometry and quantitative CT, skeletal microarchitecture will be assessed by high-resolution peripheral QCT, bone strength will be determined by finite element analysis, and the tissue material properties of cortical bone will be measured by reference point indentation periodically over the 27 months (42 months total treatment duration). If our hypotheses are confirmed, this study will successfully introduce a new framework for the treatment of osteoporosis; one that utilizes short-term combined anabolic/antiresorptive therapy followed by a single infusion of bisphosphonate to dramatically increase BMD and improve skeletal integrity over a sustained period. Positive results will provide the necessary rationale t conduct a definitive fracture efficacy study.